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Molecular Mechanism of Cotransin, a Potent and Selective Inhibitor of Protein Secretion
Author(s) -
Taunton Jack
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a147-d
Subject(s) - transmembrane protein , secretion , endoplasmic reticulum , microbiology and biotechnology , secretory protein , small molecule , cell adhesion molecule , signal transduction , chemistry , membrane protein , transport protein , receptor , biology , biochemistry , membrane
Secreted and transmembrane proteins represent the majority of current drug targets and play a dominant role in pathophysiological processes such as inflammation, angiogenesis, and metastasis. However, most secreted proteins and many transmembrane receptors are difficult to target with small‐molecule drugs. We recently synthesized a small molecule, termed “cotransin”, which potently inhibits the expression of a subset of secreted and transmembrane proteins, including the pro‐inflammatory cell adhesion molecule, VCAM. Cotransin is structurally related to the cyclodepsipeptide natural product, HUN‐7293. We discovered that cotransin blocks the cotranslational translocation of nascent VCAM chains into the endoplasmic reticulum, whereas it has no effect on the majority of secreted proteins. By a mechanism that is not yet clear, cotransin interferes with the ability of the Sec61 channel to open in response to a subset of signal sequences. Cotransin, HUN‐7293, and their structural variants offer the exciting possibility of specifically inactivating pathophysiological signaling proteins by preventing their entry into the early secretory pathway. This work was funded by the Searle and Alfred P. Sloan Foundations.